Scleroderma/systemic sclerosis (SSc) is a chronic connective tissue disease of unknown etiology. The hallmark of established SSc is widespread tissue fibrosis affecting the skin and multiple internal organs. The pathogenesis of fibrosis in SSc is complex and remains poorly understood. Vascular injury and damage, and autoimmune responses appear to be coupled with aberrant activation of fibroblasts, resulting in progressive fibrosis. Transforming Growth Factor Beta (TGF-IJ) has emerged as a central mediator of initiation and/or propagation of the fibrotic response in involved tissues. Only few underpowered studies have examined genetic polymorphisms of the TGF-fc signaling axis in the pathogenesis of SSc. We propose to take advantage of the unique patient resources and substantial expertise available at Northwestern in SSc, TGFB biology and genetics to investigate the role of two common and functionally relevant variants of TGFB1 and its signaling receptor, TGFBR1, in a cohort of 200 well characterized patients with SSc and 400 age, gender and ethnic status matched healthy controls, in order to understand the role and contribution of genetic polymorphisms of the TGF-IJ signaling pathway in the development and progression of SSc. We have the following Specific Aims: Specific Aim 1: We will assess the association between the hypomorphic TGFBR1*6A allele and SSc and its two subsets, diffuse cutaneous SSc (dcSSc) and localized cutaneous SSc (IcSSc). We will also perform haplotype analysis of the TGFBR1 gene in cases and controls. Specific Aim 2: We will genotype cases and controls for the other functionally relevant variant of the TGF-p signaling pathway: TGFB1 T29C, which results in higher TGFB1 circulating level. We will also perform haplotype analysis of the TGFB1 gene in cases and controls. Exploratory Aims: As a first exploratory aim we will analyze gene-gene interactions between the two well characterized TGFBR1 and TGFB1 polymorphisms that affect TGF-P signaling. In this Aim we will explore the relationship between the variants and risk for scleroderma. This will allow us to determine the extent to which the overall level of TGF-p signaling, as predicted by combination of these two variants, will be associated with scleroderma risk. As a second exploratory aim, we will analyze the association between disease severity and TGFBR1 as well as TGFB1 genotypes.